RNA elements directing in vivo assembly of the 7SK/MePCE/Larp7 transcriptional regulatory snRNP

Through controlling the nuclear level of active positive transcription elongation factor b (P-TEFb), the 7SK small nuclear RNA (snRNA) functions as a key regulator of RNA polymerase II transcription. Together with hexamethylene bisacetamide-inducible proteins 1/2 (HEXIM1/2), the 7SK snRNA sequesters P-TEFb into transcriptionally inactive ribonucleoprotein (RNP). In response to transcriptional stimulation, the 7SK/HEXIM/P-TEFb RNP releases P-TEFb to promote polymerase II-mediated messenger RNA synthesis. Besides transiently associating with HEXIM1/2 and P-TEFb, the 7SK snRNA stably interacts with the La-related protein 7 (Larp7) and the methylphosphate capping enzyme (MePCE). In this study, we used in vivo RNA-protein interaction assays to determine the sequence and structural elements of human 7SK snRNA directing assembly of the 7SK/MePCE/Larp7 core snRNP. MePCE interacts with the short 5'-terminal G1-U4/U106-G111 helix-tail motif and Larp7 binds to the 3'-terminal hairpin and the following U-rich tail of 7SK. The overall RNA structure and some particular nucleotides provide the information for specific binding of MePCE and Larp7. We also demonstrate that binding of Larp7 to 7SK is a prerequisite for in vivo recruitment of P-TEFb, indicating that besides providing stability for 7SK, Larp7 directly participates in P-TEFb regulation. Our results provide further explanation for the frequently observed link between Larp7 mutations and cancer development

A natural Finsler--Laplace operator

We give a new definition of a Laplace operator for Finsler metric as an average with regard to an angle measure of the second directional derivatives. This definition uses a dynamical approach due to Foulon that does not require the use of connections nor local coordinates. We show using 1-parameter families of Katok--Ziller metrics that this Finsler--Laplace operator admits explicit representations and computations of spectral data.Comment: 25 pages, v2: minor modifications, changed the introductio

RNA polymerase II stalling promotes nucleosome occlusion and pTEFb recruitment to drive immortalization by Epstein-Barr virus

Epstein-Barr virus (EBV) immortalizes resting B-cells and is a key etiologic agent in the development of numerous cancers. The essential EBV-encoded protein EBNA 2 activates the viral C promoter (Cp) producing a message of ~120 kb that is differentially spliced to encode all EBNAs required for immortalization. We have previously shown that EBNA 2-activated transcription is dependent on the activity of the RNA polymerase II (pol II) C-terminal domain (CTD) kinase pTEFb (CDK9/cyclin T1). We now demonstrate that Cp, in contrast to two shorter EBNA 2-activated viral genes (LMP 1 and 2A), displays high levels of promoter-proximally stalled pol II despite being constitutively active. Consistent with pol II stalling, we detect considerable pausing complex (NELF/DSIF) association with Cp. Significantly, we observe substantial Cp-specific pTEFb recruitment that stimulates high-level pol II CTD serine 2 phosphorylation at distal regions (up to +75 kb), promoting elongation. We reveal that Cp-specific pol II accumulation is directed by DNA sequences unfavourable for nucleosome assembly that increase TBP access and pol II recruitment. Stalled pol II then maintains Cp nucleosome depletion. Our data indicate that pTEFb is recruited to Cp by the bromodomain protein Brd4, with polymerase stalling facilitating stable association of pTEFb. The Brd4 inhibitor JQ1 and the pTEFb inhibitors DRB and Flavopiridol significantly reduce Cp, but not LMP1 transcript production indicating that Brd4 and pTEFb are required for Cp transcription. Taken together our data indicate that pol II stalling at Cp promotes transcription of essential immortalizing genes during EBV infection by (i) preventing promoter-proximal nucleosome assembly and ii) necessitating the recruitment of pTEFb thereby maintaining serine 2 CTD phosphorylation at distal regions

A measure of majorisation emerging from single-shot statistical mechanics

The use of the von Neumann entropy in formulating the laws of thermodynamics has recently been challenged. It is associated with the average work whereas the work guaranteed to be extracted in any single run of an experiment is the more interesting quantity in general. We show that an expression that quantifies majorisation determines the optimal guaranteed work. We argue it should therefore be the central quantity of statistical mechanics, rather than the von Neumann entropy. In the limit of many identical and independent subsystems (asymptotic i.i.d) the von Neumann entropy expressions are recovered but in the non-equilbrium regime the optimal guaranteed work can be radically different to the optimal average. Moreover our measure of majorisation governs which evolutions can be realized via thermal interactions, whereas the nondecrease of the von Neumann entropy is not sufficiently restrictive. Our results are inspired by single-shot information theory.Comment: 54 pages (15+39), 9 figures. Changed title / changed presentation, same main results / added minor result on pure bipartite state entanglement (appendix G) / near to published versio

Exclusive diffractive processes and the quark substructure of mesons

Exclusive diffractive processes on the nucleon are investigated within a model in which the quark-nucleon interaction is mediated by Pomeron exchange and the quark substructure of mesons is described within a framework based on the Dyson-Schwinger equations of QCD. The model quark-nucleon interaction has four parameters which are completely determined by high-energy $\pi N$ and $K N$ elastic scattering data. The model is then used to predict vector-meson electroproduction observables. The obtained $\rho$- and $\phi$-meson electroproduction cross sections are in excellent agreement with experimental data. The predicted $q^2$ dependence of $J/\psi$-meson electroproduction also agrees with experimental data. It is shown that confined-quark dynamics play a central role in determining the behavior of the diffractive, vector-meson electroproduction cross section. In particular, the onset of the asymptotic $1/q^4$ behavior of the cross section is determined by a momentum scale that is set by the current-quark masses of the quark and antiquark inside the vector meson. This is the origin of the striking differences between the $q^2$ dependence of $\rho$-, $\phi$- and $J/\psi$-meson electroproduction cross sections observed in recent experiments.Comment: 53 pages, 23 figures, revtex and epsfig. Minor additions to tex

Loneliness, social support and cardiovascular reactivity to laboratory stress

Self-reported or explicit loneliness and social support have been inconsistently associated with cardiovascular reactivity (CVR) to stress. The present study aimed to adapt an implicit measure of loneliness, and use it alongside the measures of explicit loneliness and social support, to investigate their correlations with CVR to laboratory stress. Twenty-five female volunteers aged between 18 and 39 years completed self-reported measures of loneliness and social support, and an Implicit Association Test (IAT) of loneliness. The systolic blood pressure (SBP), diastolic blood pressure (DBP) and heart rate (HR) reactivity indices were measured in response to psychosocial stress induced in the laboratory. Functional support indices of social support were significantly correlated with CVR reactivity to stress. Interestingly, implicit, but not explicit, loneliness was significantly correlated with DBP reactivity after one of the stressors. No associations were found between structural support and CVR indices. Results are discussed in terms of validity of implicit versus explicit measures and possible factors that affect physiological outcomes

An algorithm to reduce the occupational space in gender segregation studies

This paper presents an algorithm based on the bootstrap to select an admissible aggregation level, that is, the minimum number of occupational categories that yield a gender segregation value not significantly smaller than that obtained from the large number of occupational categories usually available in any data set. The approach is illustrated using labour force survey data for Spain for the comparison of gender segregation in 1977 and 1992, as well as 1994 and 2000. To measure gender segregation, an additively decomposable segregation index based on the entropy concept is used. Despite a substantial simplification in the size of the occupation space, the decrease in the segregation index is very small and not significant, regardless of the year. Consequently, intertemporal changes in gender segregation can be studied using a greatly reduced classification of occupations that permits an easier interpretation of results.Publicad

Distinct Mechanisms for Induction and Tolerance Regulate the Immediate Early Genes Encoding Interleukin 1β and Tumor Necrosis Factor α

Interleukin-1β and Tumor Necrosis Factor α play related, but distinct, roles in immunity and disease. Our study revealed major mechanistic distinctions in the Toll-like receptor (TLR) signaling-dependent induction for the rapidly expressed genes (IL1B and TNF) coding for these two cytokines. Prior to induction, TNF exhibited pre-bound TATA Binding Protein (TBP) and paused RNA Polymerase II (Pol II), hallmarks of poised immediate-early (IE) genes. In contrast, unstimulated IL1B displayed very low levels of both TBP and paused Pol II, requiring the lineage-specific Spi-1/PU.1 (Spi1) transcription factor as an anchor for induction-dependent interaction with two TLR-activated transcription factors, C/EBPβ and NF-κB. Activation and DNA binding of these two pre-expressed factors resulted in de novo recruitment of TBP and Pol II to IL1B in concert with a permissive state for elongation mediated by the recruitment of elongation factor P-TEFb. This Spi1-dependent mechanism for IL1B transcription, which is unique for a rapidly-induced/poised IE gene, was more dependent upon P-TEFb than was the case for the TNF gene. Furthermore, the dependence on phosphoinositide 3-kinase for P-TEFb recruitment to IL1B paralleled a greater sensitivity to the metabolic state of the cell and a lower sensitivity to the phenomenon of endotoxin tolerance than was evident for TNF. Such differences in induction mechanisms argue against the prevailing paradigm that all IE genes possess paused Pol II and may further delineate the specific roles played by each of these rapidly expressed immune modulators. © 2013 Adamik et al

Nonperturbative and perturbative aspects of photo- and electroproduction of vector mesons

We discuss various aspects of vector meson production, first analysing the interplay between perturbative and nonperturbative aspects of the QCD calculation. Using a general method adapted to incorporate both perturbative and nonpertubative aspects, we show that nonperturbative effects are important for all experimentally available values of the photon virtuality Q2. We compare the huge amount of experimental information now available with our theoretical results obtained using a specific nonperturbative model without free parameters, showing that quite simple features are able to explain the data.Comment: 19 page

Architecture of North Atlantic contourite drifts modified by transient circulation of the Icelandic mantle plume

Overflow of Northern Component Water, the precursor of North Atlantic Deep Water, appears to have varied during Neogene times. It has been suggested that this variation is moderated by transient behavior of the Icelandic mantle plume, which has influenced North Atlantic bathymetry through time. Thus pathways and intensities of bottom currents that control deposition of contourite drifts could be affected by mantle processes. Here, we present regional seismic reflection profiles that cross sedimentary accumulations (Björn, Gardar, Eirik and Hatton Drifts). Prominent reflections were mapped and calibrated using a combination of boreholes and legacy seismic profiles. Interpreted seismic profiles were used to reconstruct solid sedimentation rates. Björn Drift began to accumulate in late Miocene times. Its average sedimentation rate decreased at ∼2.5 Ma and increased again at ∼0.75 Ma. In contrast, Eirik Drift started to accumulate in early Miocene times. Its average sedimentation rate increased at ∼5.5 Ma and decreased at ∼2.2 Ma. In both cases, there is a good correlation between sedimentation rates, inferred Northern Component Water overflow, and the variation of Icelandic plume temperature independently obtained from the geometry of diachronous V-shaped ridges. Between 5.5 and 2.5 Ma, the plume cooled, which probably caused subsidence of the Greenland-Iceland-Scotland Ridge, allowing drift accumulation to increase. When the plume became hotter at 2.5 Ma, drift accumulation rate fell. We infer that deep-water current strength is modulated by fluctuating dynamic support of the Greenland-Scotland Ridge. Our results highlight the potential link between mantle convective processes and ocean circulationThis work is partly supported by Natural Environment Research Council Grant NE/G007632/1. RPT was supported by the University of Cambridge Girdler Fund and by BP Exploration.This is the final version of the article. It first appeared from Wiley via http://dx.doi.org/10.1002/2015GC00594